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Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218398 on 6 November 2020. Downloaded from Recommendation Points to consider for the treatment of immune-­ mediated inflammatory diseases with anusJ kinase inhibitors: a consensus statement Peter Nash ‍ ‍ ,1 Andreas Kerschbaumer ‍ ‍ ,2 Thomas Dörner ‍ ‍ ,3 Maxime Dougados,4 Roy M Fleischmann ‍ ‍ ,5 Klaus Geissler,6 Iain McInnes,7 Janet E Pope ‍ ‍ ,8 Désirée van der Heijde ‍ ‍ ,9 Michaela Stoffer-­Marx,10 Tsutomu Takeuchi,11 Michael Trauner,12 Kevin L Winthrop ‍ ‍ ,13 Maarten de Wit ‍ ‍ ,14 Daniel Aletaha ‍ ‍ ,2 Xenofon Baraliakos,15 Wolf-Henning­ Boehncke,16 Paul Emery ‍ ‍ ,17 John D Isaacs,18 Joel Kremer,19 Eun Bong Lee ‍ ‍ ,20 Walter P Maksymowych ‍ ‍ ,21 Marieke Voshaar,14 Lai-Shan­ Tam,22 Yoshiya Tanaka ‍ ‍ ,23 Filip van den Bosch,24 René Westhovens ‍ ‍ ,25 Ricardo Xavier,26 Josef S Smolen ‍ ‍ 2

Handling editor Dimitrios T ABSTRACT (PsA), axial spondyloarthritis/ankylosing spondy- Boumpas Objectives inhibitors (JAKi) have litis (AxSpA/AS), systemic erythematosus For numbered affiliations see been approved for use in various immune-mediated­ (SLE), (PsO), atopic (AD), end of article. inflammatory diseases. With five agents licensed, it was Crohn’s disease (CD), (UC) and timely to summarise the current understanding of JAKi others, have significantly improved over the past Correspondence to use based on a systematic literature review (SLR) on two decades. This results primarily from the intro- Professor Josef S Smolen, and safety. duction of several novel , in particular Division of , Methods Existing data were evaluated by a steering biological (b) disease-modifying­ antirheumatic Department of Medicine 3, Medical University of Vienna, committee and subsequently reviewed by a 29 person drugs (DMARDs), as reflected in recent manage- 1–6 1090 Vienna, Austria; expert committee leading to the formulation of a ment recommendations. Improved strategic utili- josef.​ ​smolen@meduniwien.​ ​ac.at​ consensus statement that may assist the clinicians, sation of drugs has similarly impacted positively on and Professor Peter Nash, patients and other stakeholders once the decision is outcomes. Griffith University School of made to commence a JAKi. The committee included Medicine, Herston, Gold Coast, Among all therapies developed for IMIDs over QLD 9726, Australia; ​drpnash@​ patients, rheumatologists, a gastroenterologist, a the last two decades, only tumor necrosis factor tpg.com.​ ​au haematologist, a dermatologist, an infectious disease (TNF)-­inhibitors exhibit a very broad efficacy specialist and a health professional. The SLR informed the across many diseases: RA, PsA, axSpA, juvenile Received 22 June 2020 7

Task Force on controlled and open clinical trials, registry http://ard.bmj.com/ Revised 11 September 2020 idiopathic arthritis, PsO, CD, UC and uveitis. Even Accepted 14 September 2020 data, phase 4 trials and meta-analyses­ . In addition, though targeting just a single , no other approval of new compounds by, and warnings from treatment modality has yet been approved for such regulators that were issued after the end of the SLR a broad list of indications, suggesting that TNF is search date were taken into consideration. pathogenetically involved across a diverse range Results The Task Force agreed on and developed of IMIDs. All other biological agents are licensed four general principles and a total of 26 points for fewer indications. This will likely change for consideration which were grouped into six with the advent of Janus kinase (JAK)-­inhibitors on September 29, 2021 by guest. Protected copyright. areas addressing indications, treatment dose and (JAKi), a new class of targeted synthetic DMARDs comedication, contraindications, pretreatment screening (tsDMARDs) that interfere with and risks, laboratory and clinical follow-­up examinations, pathways of a variety of and thereby have and adverse events. Levels of evidence and strengths of the potential to mediate immune modulatory bene- recommendations were determined based on the SLR fits across a broad range of pathologies and their and levels of agreement were voted on for every point, clinical phenotypes. reaching a range between 8.8 and 9.9 on a 10-point­ bDMARDs are usually monoclonal or © Author(s) (or their scale. receptor constructs that target a specific soluble or employer(s)) 2020. Re-­use Conclusion The consensus provides an assessment permitted under CC BY-­NC. No cell surface molecule, either a cytokine, a cytokine of evidence for efficacy and safety of an important commercial re-­use. See rights receptor or another cell membrane antigen. They therapeutic class with guidance on issues of practical and permissions. Published either prevent interaction of the specific with by BMJ. management. its cognate receptor, destroy a specific cell popula- To cite: Nash P, tion, such as B-­cells, or inhibit cross talk between Kerschbaumer A, particular cell populations. They have to be admin- Dörner T, et al. Ann Rheum Dis Epub ahead INTRODUCTION istered parenterally since they are proteins. They of print: [please include Day The therapeutic options for patients with immune-­ also do not enter the cell but mediate their respec- Month Year]. doi:10.1136/ mediated inflammatory diseases (IMIDs), such tive modes of action outside the cell or via the cell annrheumdis-2020-218398 as (RA), surface.

Nash P, et al. Ann Rheum Dis 2020;0:1–17. doi:10.1136/annrheumdis-2020-218398 1 Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218398 on 6 November 2020. Downloaded from Recommendation

The pathways that mediate signal trans- intracellularly and prevent the phosphorylation of JAKs. Many duction have been elucidated in recent years providing novel cytokines, such as interleukin (IL)-2, 6, 12, 15 and 23 as well as and rational targets for to modify cytokine use the JAK-­STAT pathways, while others, such as effector function. Synthetic chemical agents that interfere with IL-1, IL-17 and TNF, do not (figure 1). In addition, haemato- these pathways have been developed for various indications.8–10 poietic growth factor receptors, such as those for Among them, the JAKi represent a series of intracellularly active (EPO), and granulocyte-­macrophage colony-­ drugs, some of which have been approved for the treatment of stimulating factor, use the JAK-ST­ AT pathway (figure 1). Within several IMIDs. Five JAKi, , , , the cell usually different JAK molecules are associated with each and , are currently approved for thera- of these receptor chains, acting in tandem as heterodimers, such peutic use in one or more IMIDs in a number of geographical as JAK1 and JAK2, JAK1 and JAK3 or JAK1 and TYK2. Only in regions. the case of haematopoietic growth factor receptors both chains Our experience with bDMARDs spans two decades across carry JAK2. Thus, JAK - JAK1, 2, 3 and TYK2 - func- many diseases with thousands of patient years of experience tion as dimers and once activated phosphorylate STATs, which including in registries in many countries. In contrast, data from subsequently induce gene transcription. registries are quite limited for JAKi and some have only recently The selectivity of JAKs can be determined by using purified been approved by several regulatory authorities; safety data for systems and a variety of cellular models.18 19 Varying more than 10 years are derived mainly from long term exten- approaches may lead to differing results with respect to perceived sions of randomised clinical trials.11 12 Therefore, it was deemed selectivity of JAKs, and selectivity is dose-dependent,­ since at important to develop an evidence-­based consensus statement higher doses the compounds lose selectivity.19 20 The in vivo that focuses on practical issues in the use of JAKi. selectivity may differ further so that in vivo markers may also be helpful. Reduction of usually produces an increase in haemoglobin, as exemplified by the rapid normalisation of Scope and purpose anaemia in patients receiving monoclonal antibodies to the IL-6 Recommendations for the management of individual IMIDs receptor.21 Since EPO signals through JAK2 homodimers, failing focus primarily on therapeutic strategies and the general use to see an increase in haemoglobin in patients with anaemia of of individual or groups of agents. While quite comprehensive, chronic disease who experience clinical improvement on JAKi they usually address a particular disease and general issues, only therapy suggests an important degree of JAK2 inhibition. Of rarely accommodating the various, often complex aspects related note, failure to increase haemoglobin is not necessarily linked to to the general application of an individual drug or a specific fatigue and rarely a reason to stop a JAKi. Current views on the mode of action. Therefore, consensus statements on the more selectivity of JAKi, taking all aspects including clinical ones (such comprehensive use of specific agents or classes of drugs have also as effects on haemoglobin levels) into consideration are provided been developed.13–16 These provide more detailed information in figure 1. Of note, the totality of in vivo downstream effects on efficacy and safety of a class of drugs than in the traditional of JAKi is still insufficiently understood, especially in specific broad management recommendations. Such ‘points to consider’ disease settings, and an important matter for further research can provide prescribers, like specialists in specific disease areas, activities. and patients (especially when information is available for layper- Given that individual JAKs and STATs can be activated by sons), with an expert opinion on appropriate use of a new drug more than one cytokine, upregulation and activation of a single and its place in treatment algorithms. When a drug is approved STAT pathway does not implicate any one particular cyto-

for more than one indication, a specific consensus statement http://ard.bmj.com/ kine in a response and as such our understanding of the hier- can be used across specialties. Thus, the target of the present archical contribution of distinct STATs to effector pathways consensus statement comprises rheumatologists, dermatologists, remains conjectural. Nevertheless, success and failure of thera- gastroenterologists, other health professionals involved in these peutic trials of drugs of known selectivity enable some insights areas, patients with these respective diseases, but also hospital into pathogenesis (figure 1). For example, both IL-6 and IL-23 managers and representatives of regulators and social security receptors (R) signal via JAKs; since IL-6R­ inhibition does not agencies. appear efficacious in PsA or PsO, while IL-12 and IL-23 inhibi- These points to consider are not meant to suggest a preferen- on September 29, 2021 by guest. Protected copyright. tion is,22–24 this infers that beneficial effects of JAKi may arise by tial use of JAKi for any particular disease but rather to provide inhibiting IL-23 rather than IL-6 signalling. In contrast, IL-6R­ evidence-based­ information in conjunction with expert opinion antibodies, but not anti-IL-12/23­ antibodies,25 are efficacious once an agent of this class has been considered for the treatment in RA and, therefore, JAKi may be assumed to convey efficacy of a patient with a specific disease for which the drug is indi- by blocking IL-6 rather than IL-12 or 23 signal transduction. cated. A research agenda will complement these points to drive Moreover, neither IL-12, IL-23 nor IL-6R­ inhibition are effi- momentum to search for more evidence where this is insufficient cacious in AS,26 27 while JAKi appear to be28; consequently, this or lacking. Before addressing the methodology related to this effect cannot be explained by interference with IL-6, IL-12 or document, we will briefly allude to the mode of action and other IL-23 signal transduction, but rather by inhibition of signal pharmacological aspects of this class of drugs. transduction of other cytokines captured by JAKi (figure 1). However, also inhibition of type I (or type II) signal Mode of action transduction may play a role.29 30 Similar deliberations may be JAKs are non-­receptor tyrosine kinases associated with the made for inflammatory bowel disease, where IL-6R­ inhibition cytoplasmic domain of type I and II cytokine receptors which is not, or only weakly efficacious,31 while IL-12/23 blockade is are activated when these are engaged by their cognate ligands; efficacious,32 and for PsO.33 On the other hand, while pan JAKi once phosphorylated, they phosphorylate signal transducers is apparently efficacious in UC but not in CD,34 35 more JAK1 and activators of transcription (STATs) which then induce gene selective inhibitors (filgotinib, upadacitinib) showed promising activation.17 JAKi reversibly inhibit kinase signalling for varying results in CD,36 37 implying that differences in the pathogeneses periods of the dosing cycle. They are oral small molecules that act of these two inflammatory bowel diseases manifest in subtle but

2 Nash P, et al. Ann Rheum Dis 2020;0:1–17. doi:10.1136/annrheumdis-2020-218398 Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218398 on 6 November 2020. Downloaded from Recommendation

Figure 1 Depiction of cytokines that activate and drugs that target Janus kinases (JAKs) presumably involved in the pathogenesis of immune-­ mediated inflammatory diseases (IMIDs). Top: efficacy of agents targeting specific JAK-inducing­ cytokines in different IMIDs. Centre: cytokines and respective receptors that trigger JAKs, types of JAKs activated and type of STATs (signal transducers and activators of transcription) activated by the respective JAKs. Bottom: JAK-­inhibitors which are currently approved for IMIDs and their overall (including clinically derived) selectivity and presumed interference (+ or -) with certain cytokine pathways. axSpA, axial spondyloarthritis; EPO, erythropoietin; GM-CSF­ , granulocyte-­monocyte colony stimulating factor; IBD, inflammatory bowel diseases; IFN, interferon; IL, interleukin; ND, not done; PsA, psoriatic arthritis; PsO, psoriasis; R, receptor; RA, rheumatoid arthritis; TP, thrombopoietin.19 40 146 147 functionally important variations in the relative contribution of METHODS http://ard.bmj.com/ these signalling pathways.38 Finally while TNF does not activate The expert committee adhered to the EULAR standard oper- the JAK-­STAT pathway directly, it might do so indirectly via ating procedures for the development of recommendations.42 A 39 induction of other cytokines, such as IL-6 or type I interferons. steering committee comprising 15 members and an expanded This adds further complexity to our understanding of the patho- Task Force consisting of 14 additional individuals invited based genesis of IMIDs. on their expertise and availability and including two patient Thus, JAKi via its mode of action across signal transduction research partners (MdW, MV) and a health professional (MS-­M) on September 29, 2021 by guest. Protected copyright. of multiple cytokines is efficacious across a range of IMIDs. as well as a dermatologist (W-­HB), a gastroenterologist (MT), By corollary, this effect has potential safety repercussions (see a haematologist/haemostaseologist (KG), an infectious disease below). Clinical experience with JAKi will likely provide innova- specialist (KLW) and a fellow who performed the systematic tive insights to rewrite our understanding of IMIDs. literature review (SLR) (AK), evaluated the available data. The Among the JAKi currently approved or under study for IMIDs, clinicians were all experienced in the treatment of chronic current information on enzyme assays, cellular assays and in vivo inflammatory diseases, had participated in clinical trials of JAKi data (see above note on laboratory test results regarding JAK2 and/or bDMARDs, and several had long-­standing experience in inhibition, especially anaemia) suggest that at clinically used patient outcomes research and prior consensus statement devel- doses tofacitinib is preferentially a JAK 1, 3 and 2 inhibitor; baricitinib is primarily a JAK 1 and 2 inhibitor; peficitinib is an opment. The patients and health professionals all had experience inhibitor of JAK3 over JAK 1, 2 and TYK2; upadacitinib is a in consensus activities. There was a broad global representation JAK1 inhibitor with effects on JAK2, and filgotinib is primarily a from European countries, Asia, Australia, Latin America and JAK 1 inhibitor (figure 1).40 As mentioned above, the preferen- North America. All task force members declared their potential tial selectivity is dose-­dependent and decreases with increasing conflicts of interest and had ongoing opportunity to declare if doses as their common mechanism is to prevent ATP-mediated­ they felt conflicted throughout the process. protein phosphorylation (although a specific Drugs that had not yet undergone regulatory assessment TYK2 selective inhibitor is also under development that inhibits or formal approval but for which evidence from clinical trials signal transduction by stabilising the pseudokinase domain of the was available, could be considered in the recommendations to protein).41 anticipate potential future uptake in clinical practice, with all

Nash P, et al. Ann Rheum Dis 2020;0:1–17. doi:10.1136/annrheumdis-2020-218398 3 Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218398 on 6 November 2020. Downloaded from Recommendation respective caveats that may emerge during the approval process. needs to receive special emphasis when a drug or class of medi- Indeed, during the time of writing or revising the manuscript cines is new and long-term­ experience is still lacking. (and thus after the face-to-­ ­face meetings), two drugs, upadac- The task force further recommends to use these points-to-­ ­ itnib and most recently filgotinib, were approved (at least in consider together with general management recommendations some regions), confirming the validity of the conclusions drawn for the individual diseases which are usually provided by the on these agents in the course of the process developing the respective international or national societies (item B) and also to consensus statement. refer to the product information related to the specific disease to The steering committee and the fellow (AK) initially discussed be treated (see below item D). the research questions for the SLR which was then performed At outset, the task force decided not to provide ‘recommen- accordingly by searching the totality of the respective clinical dations’ for the use of JAKi in treatment algorithms, but rather trial literature until end of December 2018 in Medline, Embase, ‘points to consider’ assisting the clinician when thinking of Cochrane and 2018 EULAR and ACR abstracts. The details of starting, or having decided to start treatment with a JAKi (prin- the SLR are published separately.43 Cochrane risk of bias tool ciple C). Recommendations may be seen as too directive and was used. The SLR addressed RA, PsA, PsO, AS, systemic lupus would have to be brought into the context of other medications erythematosus (SLE), UC, CD, (AA)/alopecia and general treatment strategies and adjusted as new informa- universalis, and (AD). tion comes to hand in a rapidly evolving therapeutic area. In The results of the SLR were first presented to the steering contrast, the task force saw its role in elucidating important group which developed a list of proposed recommendations aspects that should be taken into account when thinking of the and/or topics to be addressed by the whole task force. The SLR prescription of a JAKi. To this end, general principles as well as and the list prepared by the steering group were then presented specific considerations are highlighted as an adjunct to product to the task force which met end of March 2019. Efficacy aspects information (principle D). were discussed by the whole task force with input from experts in respective fields. The Task Force was split into four breakout Individual points groups. One group addressed screening, the second monitoring, Six major groups of consideration are highlighted (table 1): indi- the third contraindications and the fourth adverse effects. Repre- cations; dosage and comedications; contraindications; pretreat- sentatives of each breakout group reported the results of the ment screening and risks; adverse events; and laboratory and deliberations and presented proposals for the wording of indi- clinical follow-up.­ The order within these groups does not relate vidual points to the whole task force which discussed them in to any ranking by importance but occurred either by chance or detail before voting took place. some rationale-based­ approach to therapies in general. For a general principle or point of consideration to be accepted for the final document without further change, a I. Indications majority of 75% of the votes was required in the first ballot. If JAKi have proven efficacious with acceptable safety in patients this result was not achieved, the respective text was amended with a variety of IMIDs. They have received regulatory approval and subjected to a second ballot, for which a 67% majority was for patients with RA, PsA and UC who have failed prior conven- required. If this ballot was not successful, further changes were tional synthetic DMARD (csDMARD) or bDMARD therapy, proposed until a≥50% majority was attained (or the proposal and an approval is being sought in further indications, such as rejected). The points to consider are presented in the wording dermatological, and interferonopathies. Approval of additional they were finally voted on (table 1). The results of the respec- JAKi for IMIDs is expected. At present, individual JAKi have http://ard.bmj.com/ tive last ballot are shown as percentage of present members been approved for different diseases and at varying doses, as in table 1. Notes captured the contents of the discussions and detailed below. the reasoning behind each decision to be presented in the comments accompanying the individual items in the manuscript. Data which emerged after the voting process, such as material Treatment dose and comedications in different IMIDs made public by regulators, were taken into consideration in the Treatment doses and comedications may differ between indica- tions (see below) and may have to be adjusted with higher age manuscript to provide the readers with up-to-­ ­date information. on September 29, 2021 by guest. Protected copyright. and organ (hepatic, renal) function impairment. Once the ther- After the face-to-­ ­face meeting, the points to consider as agreed apeutic target (such as remission) is reached, dose reduction or by the task force received a final adjudication in terms of level increase of intervals between doses may be considered; this dose of evidence and strength of recommendation. They were finally adjustment is not within the label of the JAKi, but similar dose changes outside the label have been suggested for bDMARDs subjected to an anonymous vote (by email) on the levels of agree- 44 45 ment. Each recommendation received an adjudication on a scale in various recommendations. In the following, we will of 0–10, 0 meaning no agreement whatsoever and 10 absolute address these aspects for the individual IMIDs for which JAKi agreement. The draft of the manuscript was sent to all task force are approved or may be licensed in the future. members for their comments which were all considered for the final version prior to submission of the manuscript. Rheumatoid arthritis Addition of a JAKi to continued (MTX) or other csDMARDs should be considered if the patient tolerates RESULTS the csDMARD,44 since—just like for all bDMARDs—there General principles is evidence for better efficacy of combination compared with The task force agreed on four general principles (table 1). The monotherapy, clinically and/or structurally.46 47 Monotherapy first of these refers to the importance of shared decision making of JAKi compared with MTX monotherapy in MTX naïve RA between the patient and the specialist, including information on patients failed to show significant structural (though not clinical) the benefits and risks of JAKi which is highlighted as principle A. superiority for baricitinib47 and—for the primary endpoint— This is in line with various management recommendations but failed to show clinical (though not structural) superiority for

4 Nash P, et al. Ann Rheum Dis 2020;0:1–17. doi:10.1136/annrheumdis-2020-218398 Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218398 on 6 November 2020. Downloaded from Recommendation

Table 1 Points to consider for the treatment of patients with immune mediated inflammatory diseases with Janus kinase (JAK) inhibitors Item Wording LoE SoR Vote (%) LoA General principles* A Initiation of JAK-­inhibitor therapy and the treatment target to be achieved should be based on a shared decision between the patient and n.a. n.a. 100 10 the medical specialist, which requires full information of the patient on the potential benefit and risks of this therapy. B Therapeutic approaches to treating patients with chronic inflammatory conditions should be in line with international and national n.a. n.a. 92 9.5 recommendations (algorithms) for the management of the respective disease. C The points to consider when initiating JAK-­inhibitor therapy do not provide information on when JAK-inhibitors­ should be used in the n.a. n.a. 92 9.8 treatment algorithm, but rather attempt to assist the clinician once the decision to prescribe a JAK inhibitor has been made. D These points to consider address specific (but not all) aspects related to the application of JAK-inhibitor­ therapy and the clinician should n.a. n.a. 88 9.8 additionally refer to the disease-­specific product information. Individual points* I Indications 1 Patients with immune mediated inflammatory diseases (IMIDs) who have failed prior conventional and/or biological therapies; as of 2019, 1a A 100 9.7 these include rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis (UC). 2 Currently, there is no direct evidence of superiority regarding efficacy or safety of one JAK-inhibitor­ over another one. 5 D 88 9.8 II Treatment dose and comedications in different IMIDs 1 Use the dose recommended for the specific disease 1a A 100 9.6 2 Consider dose adjustments in patients with higher age (>70 years), significantly impaired renal or hepatic function and/or risk of drug-­ 2b/5 C/D 100 9.7 interactions, or as a result of other comorbidities, as per individual product information. 3 Regarding comedication, follow specific recommendations for the respective disease; in RA consider adding a JAK inhibitor to continued 1a A 92 9.1 csDMARDs, if the patient tolerates the csDMARD 4 Consider dose reduction of the JAK inhibitor in RA patients in sustained CDAI or Boolean remission on background csDMARDs. 1b A 77 9 III Contraindications (consult also label and warning, see general principle D) 1 Severe active (or chronic) , including TB and opportunistic infections. 2b/5 B/D 100 9.9 2 Current malignancies. 5 D 80 9.2 3 Severe organ dysfunction, such as severe hepatic disease (Child-Pugh­ C) or severe renal disease. 5 D 100 9.9 4 Pregnancy and lactation. 5 D 100 9.9 5 Recurrent VTE (unless anticoagulated) 5 D 93 8.8 IV Pre- ­treatment screening and risks 1 Patient history and physical examination. 5 D 100 9.9 2 Routine laboratory testing (full and differential blood counts, tests (transaminases), renal function; levels at approximately 3 2b/5 B/D 80 9.3 months after initiation of therapy (and possibly at baseline unless measured within the last 12 months); no CPK testing recommended. 3 Hepatitis B testing (hepatitis B surface antigen, hepatitis B surface , hepatitis B core antibody, and with/without HBV DNA testing 5 D 92 9.8 as discussed in text). Hepatitis C testing (hepatitis C antibody, with HCV RNA testing if antibody positive) 4 Human immunodeficiency virus testing in high-­risk populations 5 D 100 9.9 5 TB screening as per national guidelines 2b B 96 9.9 6 Assess and update vaccination status. 5 D 100 9.9

7 Consider risk factors for VTE, especially a past history of VTE. 5 D 96 9.9 http://ard.bmj.com/ V Adverse events 1 Serious infections (similar to bDMARDs), opportunistic infections including TB, Herpes zoster* (increased rates compared to bDMARDs); the 2b B 100 9.9 risk of infectious events can be lowered with reduction or elimination of concomitant glucocorticoid use. 2 Rates of malignancy do not appear elevated with JAK inhibition, although the risk of NMSC may be elevated. 2b B 95 9.6 3 Lymphopenia, thrombocytopenia, neutropenia, anaemia may occur. 2b B 100 9.8 4 An increased risk of VTE has been reported in a safety trial of RA among patients using 10 mg two times a day tofacitinib and within the 2b B 94 9.5 placebo-­controlled trial period of baricitinib in patients with RA. on September 29, 2021 by guest. Protected copyright. 5 Elevations of CPK are noted with JAK inhibitors but have not been associated with clinical events. Elevations of creatinine have been noted 2b B 94 9.5 with JAK inhibitors but have not been associated with renal failure or hypertension. VI Laboratory and clinical monitoring during follow-­up. 1 Minimal laboratory monitoring: full and differential blood counts and liver transaminase tests at 1 and 3 months and then periodically, 2b/5 B/D 92 9.4 such as every 3 months; lipid levels only at month 3. 2 Annual skin examination (for detection of skin ). 5 D 83 8.3 3 Evaluate response using validated, disease-­specific measures of disease activity; for evaluation and definition of response, be aware that 2b/5 B/D 95 9.8 CRP and ESR may be reduced independently of reduction of disease activity and possibly even in infections. These bullet points have been agreed on as abbreviated summaries of the discussions and the explanatory text to each of these items should be regarded as an integral part of these points. *These points are a short abbreviation of the items discussed and presented in detail in the body of the text. They should not be applied independently of the information provided there in more detail, but present only an overview of the general scope of the consensus statement. The percentages shown reflect the proportion of participants who approved the respective bullet point during the voting at the task force meeting. Some items carry two levels of evidence, because part of the respective points have only the level of expert opinion (level 5), namely II/2: comorbidities not studied, since most excluded from trials; III/1: patients with chronic infections (even if mild) were not studied; IV/2and VI/1: proposed intervals not studied; VI/3 blunting of the acute phase response during infections not sufficiently studied. bDMARD, biological disease-­modifying antirheumatic drug; CDAI, Crohn’s Disease Activity Index; CPK, creatine phosphokinase; CRP, C reactive protein; csDMARD, conventional synthetic disease-­modifying antirheumatic drug; HBV, hepatitis B virus; HCV, hepatitis C virus; LoA, levels of agreement; LoE, level of evidence; n.a., not available; NMSC, non-melanoma­ skin cancer; SoR, strength of recommendation; TB, ; VTE, venous thromboembolism. filgotinib,48 while achieved significant had significantly better clinical and structural efficacy than MTX superiority across all outcomes. On the other hand, mono- monotherapy,49 50 but neither was investigated in 3-arm­ trials therapy of tofacitinib and upadacitinib in MTX naïve patients with an additional combination arm. In contrast, filgotinib was

Nash P, et al. Ann Rheum Dis 2020;0:1–17. doi:10.1136/annrheumdis-2020-218398 5 Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218398 on 6 November 2020. Downloaded from Recommendation assessed in a 3-­arm trial in MTX-­naive RA patients; while at baricitinib versus , subanalyses revealed that this both the 100 mg and 200 mg dose filgotinib plus MTX attained superiority was primarily seen for patient-­reported outcomes, the primary endpoint of superiority against MTX monotherapy, but not for joint counts.58 No dose adjustment is needed for filgotinib monotherapy at 200 mg failed to show statistical supe- renal impairment, but with severe hepatic impairment the drug riority compared with MTX monotherapy (filgotinib 100mg as is contraindicated. monotherapy was not tested), 1 48 None of the JAKi has ever been More recently, filgotinib was approved at 100 mg and 200 mg compared with MTX plus glucocorticoids, the standard therapy doses in Europe59 and in Japan. In contrast, FDA did not recommended by EULAR for over a decade44 which has not been approve filgotinib wishing to await data from spermatogenesis shown to be inferior to bDMARDs plus MTX.51 52 However, safety studies and raising concern about the safety of the 200 mg a JAKi can be given as monotherapy in case of intolerance or dose.60 Filgotinib has completed phase 3 clinical trials at 100 mg contraindications to MTX and other csDMARDs. and 200 mg daily. Data of a study comparing filgotinib plus MTX The recommended dose of tofacitinib for RA is 5 mg two head to head with adalimumab plus MTX recently became avail- times a day in most countries; at this dose tofacitinib was supe- able and revealed non-­inferiority for DAS28-­C reactive protein rior to placebo in patients with active disease despite MTX or (CRP) <3.2 for the 200 mg, but not the 100 mg dose; it was not prior bDMARD therapy, and in a head to head study tofacitinib possible to claim superiority versus adalimumab plus MTX due 5 mg two times a day combined with MTX was non-inferior­ (but to the statistical plan.61 Filgotinib has also been studied as mono- not superior) to adalimumab combined with MTX while mono- therapy (see above). therapy of tofacitinib 5 mg two times a day failed to show non-­ Peficitinib showed significant efficacy on symptoms, signs and inferiority to either combination therapy with tofacitinib plus structural outcomes of RA in randomised trials including mono- 46 MTX or adalimumab plus MTX. Of note, according to infor- therapy and concomitant MTX treatment, in patients with an mation by regulatory authorities tofacitinib at 10 mg two times IR to TNFi and an open label study with as a safety a day was associated with an increased venous thromboembo- control. These studies included a majority of Japanese, Korean lism (VTE) and (PE) rate in patients with and Taiwanese patients,62 63 while the difference to placebo was RA enriched for cardiovascular risk factors,53 54 and a similar 55 small in a global study where very high placebo response rates warning was also issued for 5 mg two times a day (see also were seen.64 Peficitinib is approved in Japan and Korea at 100 below). In addition, the dose should be reduced in patients with and 150 mg daily. a creatinine clearance (CrCl) of <30 mL/min and is contraindi- The dose of JAKi should be modified according to patient-­ cated in patients with severe hepatic impairment (Child Pugh C). specific demographics, comorbidities and/or concomitant medi- The recommended dose of baricitinib in RA is 4 mg once daily cations as per product monograph inserts (see also section on (except for some countries such as USA, Canada and China, contraindications). where it is 2 mg daily). At the 4 mg dose in combination with There is no evidence at present that one JAKi is more effica- MTX, it showed superior efficacy to placebo (or de novo MTX) cious clinically, functionally or structurally or safer than another in all RA patient populations, MTX/csDMARD-insufficient­ JAKi. While two studies have shown superior efficacy of a JAKi responders (IR), bDMARD-­IR or MTX-naïve,­ respectively; in plus MTX compared with an anti-­TNF plus MTX,56 58 two most countries the approval is for these populations apart from other trials have failed to show such effect46 61; moreover, in the MTX-­naïve patients, as combination therapy or monotherapy. trials showing superiority of a JAKi plus MTX to adalimumab A dose of 2 mg once daily is appropriate for patients aged ≥75 plus MTX, the significantly better efficacy was seen for most years, those with a CrCl of 30–60 mL/min and may be appro- 56 58

outcomes, but not for tender and swollen joint counts. Thus, http://ard.bmj.com/ priate for patients with a history of chronic or recurrent infec- the relevance of this finding is currently limited; moreover, as of tions. In a head to head study baricitinib 4 mg per day combined now, no study compared one JAKi with another. On the other with MTX had superior efficacy compared with adalimumab hand, several of the above cited studies clearly revealed that JAKi 40 mg combined with MTX.56 Subanalyses revealed that this have superior efficacy than TNFi for pain and fatigue, an aspect superiority was primarily seen for patient reported outcomes, that deserves further investigation, as it may relate to a hitherto but not for joint counts. In a tapering study patients in long-term­ insufficiently recognised and specific mode of action for this low disease activity or remission after 15 months therapy could on September 29, 2021 by guest. Protected copyright. reduce baricitinib to 2 mg per day; low disease activity (LDA) was . maintained at 12 weeks after step down in 83% of patients; 90% No studies are yet available in JAKi IR or intolerant patients switching from one JAKi to another JAKi. However, a recent of those who flared regained their original response after dose 65 increase.57 Combination of baricitinib with MTX had signifi- study showed efficacy of anti-­TNF therapy after IR to a JAKi, cantly better structural outcomes compared with MTX alone, and safety regarding switch from a bDMARD to a JAKi without but—while monotherapy was similar to combination therapy washout, information that was missing hitherto. in terms of clinical and functional outcomes—structural benefit Regarding dose reduction in patients with RA in sustained was not significant for baricitinib monotherapy.47 Clinical Disease Activity Index (CDAI) or Boolean remission on Since the date of the SLR, upadactinib has been approved by background csDMARD, trial evidence is currently confined to 57 FDA and EMA at 15 mg daily. At this dose, it showed superior dose reduction for baricitinib. efficacy to placebo (or de novo MTX) in all RA patient popu- lations, MTX-­IR, bDMARD-IR­ or MTX-­naïve, respectively. In Psoriatic arthritis most countries, the approval is for these populations except for Currently, only tofacitinib is approved for PsA; the licensed dose MTX-­naïve, as combination therapy or monotherapy. A upadac- is 5 mg two times a day. The clinical trials demonstrated efficacy itinib monotherapy study in patients with IR to MTX had high in patients with prior IR to csDMARDs66 and TNFi.67 The effi- response rates but lacked a comparator group of upadacitinib cacy in PsO is described below. combined with MTX.49 In combination with MTX, upadaci- Since the closing date of the SLR, two phase 3 trials of upad- tinib 15 mg provided superior efficacy compared with adalim- acitinib were completed successfully, showing efficacy regarding umab plus MTX in a head to head study.58 As in the study of main outcomes of PsA, also when compared with adalimumab

6 Nash P, et al. Ann Rheum Dis 2020;0:1–17. doi:10.1136/annrheumdis-2020-218398 Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218398 on 6 November 2020. Downloaded from Recommendation

(non-­inferiority for the ACR20 response with the 15 mg and difference among patients exhibiting at least a 75% improve- superiority with the 30 mg dose).68 69 ment in their PASI (PASI75) when compared with placebo was Filgotinib at 200 mg daily showed efficacy in a phase 2 trial70 observed for patients receiving 8 or 10 mg daily (43% and 54% and phase 3 data are awaited. vs 17%),75 a much higher dose than approved for RA and, again even at this dose the skin response is numerically lower than reported for several of the more recently approved bDMARDs; Tofacitinib demonstrated significant efficacy at 12 weeks for for example, for IL-12/23 inhibitors the PASI75 amounted to signs and symptoms in patients with highly active AS (by modi- about 70% and 80% for and guselkumab, respec- fied New York criteria) refractory to NSAIDs in a phase 2 dose-­ tively,.76 77 and to 89% on IL-17 inhibition.78 ranging placebo-­controlled RCT. The highest Assessment of For the JAK1 inhibitors , itacitinib and GSK2586184 SpondyloArthritis international Society (ASAS) 20 response was as well as the JAK1/3 inhibitor peficitinib, data in the public observed at 5 mg two times a day, especially in patients with both domain are equally available from one phase II study each. 60% elevated CRP and evidence of MRI inflammation in the sacro- of patients receiving the most effective dose regimen (200 mg iliac joints.71 A dose-­dependent effect for clinical response was twice daily) of abrocitinib experienced a 75% improvement of not evident. Separation from placebo was observed at 4–8 weeks the PASI.79 Itacitinib showed significant improvement in the suggesting a slower onset of response than seen with TNFi. Physician Global Assessment (PGA) after 4 weeks of treatment Filgotinib at 200 mg once daily has been assessed in patients with 600 mg once daily versus placebo,80 while GSK2586184 with active AS refractory to NSAIDs and TNFi (10%) in a at 400 mg once daily yielded a 75% PASI improvement in 57% 12 week phase 2 placebo-controlled­ RCT.28 Significant benefit of patients after 12 weeks,81 and patients treated with 50 mg of for disease activity, assessed by the AS Disease Activity Score peficitinib once daily benefitted from improved PASI, PGA and (ASDAS), was evident by week 1 and major improvement in reduced body surface area affected.82 ASDAS was noted in 33% versus 2% of patients on filgotinib and Another JAKi, , was tested in two topical formu- placebo, respectively, at 12 weeks. For most outcomes separation lations containing 1% and 1.5% of ruxolitinib, respectively, from placebo was observed at 4–8 weeks. versus placebo and two active comparators, namely calcipot- Upadacitinib at 15 mg daily was assessed in a 12-week­ phase riene 0.005% cream and betamethasone doproprionate 0.05% 2/3 placebo-­controlled trial that recruited patients with active AS cream. A statistically significant difference versus the vehicle refractory to NSAIDs.72 Significantly more patients had an ASAS was observed after 4 weeks of treatment for the ruxolitinib 1% 40 response at week 14 in the upadacitinib versus the placebo group, with comparable efficacy of ruxolitinib formulations with group (52% vs 26%) and this was observed at the first post- the active comparators.83 baseline visit at week 2. Other outcomes including MRI spine For two additional JAKi, no peer-­reviewed publicly available and sacroiliac joint inflammation, were also superior for upadac- data have been published so far. itinib, just like for tofacitinib and filgotinib. Finally, a phase II study evaluating the TYK2 inhibitor Overall, the 12-week­ phase 2 data support the efficacy of BMS-986165 was recently published.41 Doses ranging from 3 mg JAKi for a variety of disease outcomes relevant to AS to a degree every other day up to 12 mg daily were studied and compared comparable to TNFi while the pattern of AEs and changes in with placebo. BMS-986165 at doses of 3 mg daily and higher laboratory outcomes were similar to those reported in previous was found to result in greater clearing of PsO than did placebo studies in other indications. over a period of 12 weeks, with PASI75 responses up to 75% in

the highest dose group. Data for two additional TYK2 inhibitors http://ard.bmj.com/ Dermatological diseases including PsO await peer-­reviewed publication. Nine different JAKi and three selective TYK2 inhibitor have Evidence for therapeutic efficacy of JAK-inhibitors­ or TYK2-­ been evaluated in PsO; none of them has been approved for this inhibitors has also been suggested in several other immune-­ indication to date except for occasional individual countries, mediated inflammatory dermatoses, including atopic dermatitis, 84 such as Russia (tofacitinib). alopecia areata, , palmoplantar pustulosis and a case of Tofacitinib was tested in one phase II, four phase III and one a mucocutaneous disease called idiopathic erythema multiforme

85 on September 29, 2021 by guest. Protected copyright. long-term­ extension study, the results of which were recently associated with a mutation in TRPS1 and JAK-­STAT activation. summarised.73 Tofacitinib 5 and 10 mg two times a day showed Taken together, PsO belongs to a group of chronic inflam- superiority over placebo for all efficacy endpoints at week 16, matory skin diseases for which inhibition of JAKs or TYK2 has with response maintained for 52 weeks of continued treat- shown clinical efficacy. However, the extent of efficacy observed ment. The Psoriasis Area and Severity Score (PASI) response, and the safety profile of the JAKi has so far not led to drug however, appeared numerically lower than that typically seen authorisation by EMA or FDA, but there is considerable interest for bDMARDs such as IL-12/23 or IL-17 inhibitors. Tofacitinib around TYK2 inhibition, given the absence of some safety issues improved patients’ quality of life and was well tolerated. With linked to non-­selective JAKi, as well as regarding indications the exception of herpes zoster, rates of safety events of interest other than PsO, namely AD, where there are still far less options were similar to those in the published literature and health- available for systemic therapies. care databases for other systemic PsO therapies. Tofacitinib 10 mg two times a day demonstrated greater efficacy (PASI75 Inflammatory bowel disease at 12 weeks: 43% in MTX-IR­ and 21% in TNFi patients) than Tofacitinib is indicated for the treatment of adult patients with 5 mg two times a day. An additional phase IIa study evaluating moderately to severely active UC who have had an inadequate topical application of tofacitinib in mild-to-­ ­moderate PsO found response, lost response or were intolerant to either conventional significant clinical improvement over placebo treatment after 4 therapy or a biologic agent.34 Tofacitinib 5, 10 and 15 mg two weeks.74 times a day showed significant efficacy for remission (Mayo Baricitinib was studied in a phase IIa dose-ranging­ study, score) in patients who were cs- and bDMARD-­IR.86 The recom- using once daily dosing over 12 weeks. A statistically significant mended dose is 10 mg given orally twice daily for induction for 8

Nash P, et al. Ann Rheum Dis 2020;0:1–17. doi:10.1136/annrheumdis-2020-218398 7 Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218398 on 6 November 2020. Downloaded from Recommendation weeks (or 16 weeks if adequate benefit is not achieved) and 5 mg Table 2 Dosing and metabolisation of the different Jakinibs given twice daily for maintenance (in TNFi-IR­ patients 10 mg two times a day maintenance may be used). The 10 mg two times Approved a day dose was associated with VTEs and PEs in patients with Drug Dosage indications RA53 (see also below). Tofacitinib RA, PsA: 5 mg bd, RA, PsA, UC CyP3A4; Upadacitinib and peficitinib similarly have shown efficacy in 11 mgs ER daily; 30% renal UC: 10 mg two phase 2 trials in csDMARD and bDMARD-IR­ patients in dose-­ times a day ranging studies of UC.87 88 Baricitinib 2 or 4 mg daily RA >66% renal excretion In CD, tofacitinib at 5–15 mg two times a day has shown no Upadacitinib 15 mg daily RA CyP3A4; significant efficacy in induction and maintenance of Crohn's 20% renal excretion disease activity index remission (<150) compared with 35 Filgotinib 100 or 200 mg RA CES2 ; active metabolite placebo. However, selective JAK1 inhibition by filgotinib daily 1:10 potency showed increased remission rates in patients with moderate to Peficitinib 100 or 150 mg RA NNMT, SULT2A1; 36 severe CD. Moreover, upadacitinib also showed promising daily 16% renal excretion 37 results in a phase II trial in CD and larger phase III trials have Ruxolitinib 5–25 mg two times Polycythaemia rubra CyP3A4, CyP2C9 been initiated. Collectively, these findings hold promise for these a day vera agents as clinical therapeutics in IBD which await corroboration Myelofibrosis in ongoing phase III trials. CES2, carboxylesteraseisoform 2; Cyp, cytochrome P; ER, extended release ; NNMT, nicotinamide N‐methyltransferase; PsA, psoriaticarthritis; RA, rheumatoid arthritis; SULT2A1, sulfotransferase 2A1; UC, ulcerative colitis. Other diseases Baricitinib was investigated in a phase 2 trial of systemic lupus erythematosus and demonstrated significant efficacy at 4 mg but 4. Consider dose reduction in sustained remission on back- not 2 mg compared with placebo.89 ground therapy Other indications for which JAKi are being evaluated include This aspect has also been addressed in the previous section. non-­infectious uveitis, CANDLE syndrome and other inter- For dose adjustments due to impaired organ function see below. feronopathies, including USP18 deficiency.90–92 The reader is referred to the SLR manuscript.43 III. Contraindications that should be considered Contraindications are primarily related to the adverse event and II. Treatment dose and comedication the pharmacokinetic/pharmacodynamic profile of the various JAKi. 1. Use the dose recommended for the specific disease. 1. Severe active infections, acute or chronic, including latent The dosing of individual JAKi in the various diseases has been TB and opportunistic: these infections can be seen in pa- addressed in the previous section (see above). tients treated with JAKi.93 Serious rates in RA and PsA studies of tofacitinib, baricitinib and upadacitinib were comparable to adalimumab with higher rates occurring at 2. Dose adjustments due to drug interactions higher doses.12 93 Tofacitinib treated RA patients above 65 years (with cardiovascular risk factors) exhibited a higher Tofacitinib is metabolised by the hepatic cytochrome P (CYP) rate of serious infections compared with TNFi treated pa- http://ard.bmj.com/ 450 pathway which leads to drug interactions with inhibitors tients and according to EMA tofacitinib should be used in such as and promoters such as , neces- these patients only if there is no other alternative.94 A recent- sitating dosage adjustments, although it is also 30% renally ly published post hoc analysis of RA trial data that included excreted. In contrast, baricitinib is 70% renally excreted. Filgo- an adalimumab comparator found similarly increased risks tinib is metabolised by hepatic carboxylesterases and has a major for serious infections among the elderly, particularly among metabolite GS-829845 which is a pharmacologically active, those using 10 mg two times a day tofacitinib. Risk elevations on September 29, 2021 by guest. Protected copyright. selective inhibitor of JAK1, but is 10–20 times less potent than as compared with younger patients were similar for those the parent compound. Upadacitinib predominantly undergoes using adalimumab and tofacitinib 5 mg two times a day, but hepatic oxidation with minor CYP metabolism and peficitinib several fold higher for those using 10 mg two times a day.95 undergoes hepatic conjugation. Organic anion transporter 3 2. Malignancy: using a JAKi in this situation should be a shared inhibitors, such as probenecid, interact with baricitinib requiring decision with the patient given timing of past malignancy, a dose reduction to 2 mg per day (with normal renal function). uncontrolled malignancy or ongoing treatment with chemo- Rifampicin when used in latent tuberculosis (TB) prophylaxis therapy including checkpoint inhibitors. Thus far, patient or therapy for active TB increases hepatic metabolism of tofaci- registries and data have demonstrated no ma- tinib and upadacitinib so that a dose increase of the latter has to lignancy signal. There are no data to suggest that prior ma- be considered. Ketoconazole has the opposite effect, inhibiting lignancy is problematic with JAKi therapy, but most studies tofacitinib and upadacitinib metabolism so a dose reduction is excluded patients with malignant disease up to 5 years prior suggested. Dose adjustments due to hepatic or renal impairment to enrolment. are discussed below. 3. Severe organ dysfunction: With severe hepatic disease (Child-­ The dosing of the individual agents and their metabolisation Pugh C), JAKi should not be used. With respect to severe are summarised in table 2. renal disease (CrCl) <30 mL/min), a reduction in dosage is 3. Comedication recommended for tofacitinib to 5 mg once daily; baricitinib is Comedication has been addressed in the previous section, not recommended if CrCl is <30mL/min. With CrCl 30–60 including addition of JAKi to pre-­existing csDMARDs as combi- mL/min baricitinib should be used at 2 mg daily. No dosage nation therapy. reduction is currently recommended for other JAKi.

8 Nash P, et al. Ann Rheum Dis 2020;0:1–17. doi:10.1136/annrheumdis-2020-218398 Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218398 on 6 November 2020. Downloaded from Recommendation

4. Pregnancy and lactation: Limited data are available and con- gested unless recently checked. No creatine phosphokinase traception while taking JAKi is advised for both female and (CPK) testing is needed. male patients in the absence of adequate data. Tofacitinib has 3. Hepatitis B virus (HBV) testing for anti-­HBs, anti-HBc,­ and been shown to be teratogenic in rats and rabbits, and to af- HBsAg is recommended in all patients. Patients with evi- fect parturition and peri/postnatal development.96 dence of chronic HBV infection (ie, positive HBsAg) should Filgotinib reduces spermatogenesis in a dose-dependent­ avoid JAKi or treatment with biologics if possible. If not manner in animal studies; to date, this has not been observed possible, then concomitant treatment or prophylaxis with an in humans, but a definitive study evaluating this question is anti-­viral (eg, entecavir, tenofovir or tenofovir alafenamide) currently underway97 so this can then be taken into account should be undertaken alongside consultation with a hepatol- appropriately in male patients. ogist.100 For patients with evidence of prior HBV exposure These agents have short plasma half-lives­ but a gap of 4 (positive HBc antibody) and no evidence of active viral repli- weeks is recommended after the last dose if future pregnancy cation (ie, negative HBsAg), a baseline HBV DNA should be is being contemplated. It is not known whether tofacitinib is obtained to rule out occult active HBV infection. If positive, secreted in human milk, but it is secreted in the milk of lac- then patients have active HBV and should be managed ac- tating rats. A risk to the breast-­fed child therefore cannot be cording to the above. The main virological event of concern excluded. As a precautionary measure, the use of tofacitinib in these anti-HBc­ positive patients is HBsAg reappearance during breast-­feeding is contraindicated. (seroreversion), consistently associated with hepatitis flare; A study of a small number of patients with UC taking tofac- HBV DNA detection (without HbsAg) leads to seroreversion itinib observed healthy newborns, no foetal or con- and hepatitis in 50% of cases.100 If HBV-DNA­ negative, then genital malformations and spontaneous abortions appeared such patients can start JAKi and should be routinely moni- consistent with background risks in the USA.98 Similar data tored for HBV DNA and HBsAg reappearance (serorever- exist for RA and PsO.99 sion) in line with respective national recommendations for 5. History of VTE events: in patients with a history of throm- TNFi. If HBV DNA or HBsAg subsequently turns positive boembolic events initiation of a JAKi should be carefully during monitoring, then the patient should be managed as evaluated based on the increased rates of VTEs in patients above with referral to a hepatologist for treatment. The JAKi at risk for these events (see below under risks and adverse should be temporarily stopped until full evaluation can be events). Increased VTEs, especially PE, have been observed made. Concurrent treatment with an antiviral is possible, in patients with cardiovascular risk factors treated with 10 mg and the JAKi can be reinstituted once anti-viral­ therapy has tofacitinib two times a day53 54 indicating that also these (ar- been started.101 terial) risks require consideration. Patients with recurrent Hepatitis C virus (HCV) antibody testing is recommended thromboembolic events will usually receive anticoagulation and should be further assessed if positive, that is, HCV RNA treatment likely counteracting the risk. testing. If positive, then the patient has active HCV and The safety and efficacy of JAKi is under investigation in juve- should be referred for treatment. In such case, JAKi should nile patients but has not yet been established in persons <18 be withheld until HCV treatment has been completed. years of age. For restrictions regarding patients >65 years of age 4. HIV testing is recommended for those with HIV risk factors. see below. 5. As the risk for TB-­reactivation with JAKi is similar to that Finally, JAKi have not been studied and, therefore, are not for TNFi, screening for TB is recommended, unless already recommended in combination with bDMARDs or potent immu- done prior to bDMARD commencement without a risk of nosuppressive agents such as cyclosporine or because exposure since then. All patients in JAKi phase 3 studies were http://ard.bmj.com/ of the possibility of increased and increased screened for TB and patients with active TB excluded while risk of infection or . patients with latent TB were commenced on anti-­TB thera- I V. Pretreatment screening and risk assessments py and included. Cases of TB were noted with JAKi more 1. History and physical examination: Important patient de- commonly than with placebo in pivotal trials, with at least tails to obtain before starting therapy include a history some cases occurring in endemic areas likely representing and risk estimation of VTE, infections, TB, risk factors newly acquired infection rather than reactivation of prior on September 29, 2021 by guest. Protected copyright. for hepatitis B and C, as well as usual medical consider- infection.12 93 ations such as comorbidities, cardiovascular risk factors 6. Vaccination status should be sought. Country and regional and concomitant medications of relevance, for example, vaccination guidelines should be followed. EULAR has re- Cox 2 inhibitors, prednisone doses >7.5 mg daily or oral cently updated its vaccination recommendations for patients contraceptives. with autoimmune diseases.102 In addition to Herpes zoster The recommendation for patients over 70 years of age is a reactivation, and cytomegalovirus reactiva- baricitinib dose reduction to 2 mg daily due to age-related­ re- tion may also occur. HPV reactivation is not known to occur, ductions in renal function. Moreover, EMA has restricted the but has not been evaluated systematically. use of tofacitinib in people older than 65 years also due to Herpes zoster reactivation: A history of varicella or zoster an increased risk of serious infections.94 No dose reduction is infection or immunisation should be obtained. Herpes zoster recommended for modest renal impairment with upadacitin- reactivation is clearly increased under JAKi with incidence ib and filgotinib therapy. rates (IRs) between 3–4 (Western Europe, USA, Australia) Baseline skin check for non-melanoma­ skin cancer (NMSC) and 9 (Japan, Korea) per 100 patient-­years compared with in patients at risk and chest X-ray­ is also recommended, un- 2–3 per 100 patient-­years for TNFi. Risk factors include age, less recently performed. female gender, prednisolone >7.5 mg per day, infection and 2. Routine laboratory testing that includes a full blood count hospitalisation.11 12 103–106 As for serious infections, there is (including a differential white cell count), liver enzymes (in also a dose response for Herpes zoster reactivation. The reac- particular transaminases), and renal function tests are rec- tivation is likely based on the mode of action of JAKi block- ommended before starting JAKi. Baseline lipid levels are sug- ing interferon pathways. If a patient develops Herpes zoster,

Nash P, et al. Ann Rheum Dis 2020;0:1–17. doi:10.1136/annrheumdis-2020-218398 9 Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218398 on 6 November 2020. Downloaded from Recommendation

JAKi treatment should be temporarily interrupted until the Their frequency is dose and co-­ dependent and episode resolves. A small proportion of patients can develop the reactivation of Herpes zoster is more frequent than on recurrent zoster. Antiviral prophylaxis could be considered bDMARDs and especially frequent in Japan and Korea. in such individuals. Moreover, EMA (but not FDA) has restricted the use of to- Evidence for the efficacy of the live Zostavax is facitinib in people older than 65 years due to an increased questionable and as a live attenuated vaccine it necessitates risk of serious infections.94 Herpes zoster was also seen with a delay of 3–4 weeks postvaccination before starting a JAKi; baricitinib and less commonly with upadacitinib. It is also further, a single missed dose of MTX could be considered, listed as an important potential risk for filgotinib by EMA, since MTX may blunt the antibody response,107 but this ap- and while they state that no signal for varicella zoster infec- proach is not evidence based. In a live zoster vaccination tion has been detected in the filgotinib RA clinical trial pro- study, zoster IRs at follow-up­ were numerically similar in the gram, the agency requests further evaluation by additional 117 tofacitinib 5 mg and adalimumab and MTX arms but higher pharmacovigilance activities. rates were seen for the combination of tofacitinib 5 mg two 2. Malignancy: The overall rates are not increased except for times a day with MTX.108 Notably, zoster rates at follow-up­ the risk of NMSC which might be elevated and, therefore, were generally similar in vaccinated versus non-vaccinated­ the task force recommends regular skin examinations, es- patients, but further studies are clearly needed. While the vac- pecially in countries with increased risk of NMSC, such as cination resulted in reasonable immune responses, 1 patient Australia. The task force also felt that current malignancy developed zoster infection having had no prior immunity.109 (except NMSC and cervical carcinoma in situ undergoing A new zoster vaccine has been more recently approved; be- treatment) may be a contraindication for JAKi, but as stated ing a nonlive vaccine, it is not contraindicated in patients previouly, this should be a shared decision making with the receiving immunosuppressive or immunomodulating agents, patient. but currently there are no data on safety and protective im- 3. Anaemia and cytopenias: Anaemia of chronic disease, as munogenicity of this vaccine in patients treated with JAKi. usually seen in most IMIDs, does not improve on the group As studies are underway, these questions should be resolved level with all JAKi except for filgotinib, and in some patients soon. The safety of the inactivated zoster vaccine (Shingrix) the pre-existing­ anaemia may deteriorate, presumably due to has been suggested by a small open label study of 400 pa- JAK 2 inhibition; JAK 2 is involved in EPO signalling (see figure 1). Cytopenias may occur but were not more frequent tients with RA (no zoster activation, 6.7% disease flares, 12 mostly mild, self-limiting,­ and not requiring therapeutic than on placebo, although with all JAKi a few patients may change), but efficacy and immunogenicity of the vaccine in exhibit neutropenia and/or lymphopenia. this setting is unknown.110 4. VTE/pulmonary embolism (PE). Across indications, in ran- 111 112 domised controlled trials and long term extensions of to- 7. Risk factors for VTEs should be considered by history facitinib followed for up to 9.5 years, no increased risk of and a potential clotting abnormality should be pondered in VTE for the 5 mg bd dose has been seen.11 54 However, in patients with a history of VTEs in whom such assessments a still ongoing safety study of patients with RA enriched for have not yet been done. While these events are rare, the risks cardiovascular risk factors, a statistically significant PE im- are increased in patients with prior VTEs; with increasing balance for tofacitinib 10 mg bd as compared with 5 mg two age (patients older than 65 years are at higher risk for having times a day was demonstrated with an absolute IR of 0.5 VTEs with tofacitinib); (people with obesity have two for 10 mg and 0.3 for 5 mg53–55; compared with TNFi (ab-

times the risk of VTEs as people with normal weight, and the http://ard.bmj.com/ solute IR of 0.1) which were investigated as a control arm, higher the weight, the higher the risk); prolonged immobility the PE risk thus being about threefold higher for the 5 mg (ie, long travel, lower-extremity­ paralysis due to spinal cord dose and about sixfold higher for the 10 mg dose.54 94 In this injury, trauma with reduced mobility); hereditary (ie, factor same study, as reported by the EMA, VTE without PE were V Leiden, prothrombin mutation 20210, etc) and acquired somewhat numerically higher with tofacitinib than TNFi but (ie, antiphospholipid syndrome, malignancy) thrombophilia; the difference was not statistically significant. Since this is an Cox 2 inhibitor therapy113 114; prednisolone of ≥7.5 mg/d ongoing study, the full data for the 5 mg dose will have to be on September 29, 2021 by guest. Protected copyright. and above; major surgical interventions, such as neurosurgic, awaited for a full assessment of the VTE risk, but the 10 mg urologic, gynaecologic and orthopedic surgery. Interestingly, two times a day dose was discontinued in this study. A recent a recent study from Sweden suggested that VTEs are signifi- analysis of VTE/PE in clinical trials of UC in which most of cantly related to disease activity with an adjusted RR of 1.99 the patients had been treated with a dose of 10 mg two times during high, 1.45 during moderate and 1.11 with low RA 114 115 a day reported that during the placebo controlled period no activity compared with remission. This potential rela- UC patient had a VTE or PE and 1 VTE and 1 PE each were tion between VTE rates and RA disease activity remains to seen in placebo treated patients.118 During the long term, be fully elucidated. For more details regarding VTEs and PEs open-­label extension comprising about 2400 patient-­years see below under adverse events. of exposure, 1 patient had a VTE and 4 had PEs, all with risk factors for these events.118 The recent EMA assessment V. Adverse events provided evidence for an increased PE risk at the 5 mg and Adverse events are mainly related to the inhibition of cellular especially the 10 mg two times a day dose of tofacitinib.55 pathways and include those already mentioned above under The FDA has not made a final determination and is awaiting risks. However, several other adverse events need more detailed the final, adjudicated results of the study. consideration. Baricitinib at 4 mg had an imbalance in VTEs compared with 1. Serious infections including opportunistic infections such as the control arms (placebo or adalimumab) in the controlled TB and others, as well as reactivation of Herpes zoster and period of RA trials; this has not been observed with the 2 mg other viruses can occur. The IR of Herpes zoster reactivation dose.49 119 Risk factors were age, high BMI, immobilisation, amounts to about 3–4 compared with placebo (IR=1).115 116 surgery, use of Cox-2 inhibitors and a history of prior VTEs;

10 Nash P, et al. Ann Rheum Dis 2020;0:1–17. doi:10.1136/annrheumdis-2020-218398 Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218398 on 6 November 2020. Downloaded from Recommendation

the risk may be up to 10-fold­ for patients with a history of patients who may be at increased risk for gastrointestinal perfo- VTEs and twofold for those patients taking Cox2 inhibi- ration (eg, patients with a history of diverticulitis and taking tors.120 Subsequently, there was no increase in risk when pa- concomitant NSAIDs or glucocorticoids). Patients presenting tients were transitioned from placebo or MTX to baricitinib with new onset abdominal signs and symptoms should be evalu- as well as across long-term­ extension studies over 6 years ated promptly for early identification of gastrointestinal perfo- but VTEs in the LTE were observed equally with 2 and 4 mg. ration knowing fever and elevation of acute phase reactants may Numerically increased rates of VTEs have also been observed be blunted by JAKi therapy. in the double blind phases of upadacitinib trials, primarily with the 15 mg once a day dose, although not in the head-­to-­ head trial against adalimumab.49 58 119 With respect to filgo- VI. Laboratory and clinical monitoring during follow-up tinib, EMA regards VTE as a potential risk, but the agency 1. As a minimal laboratory monitoring during follow-up,­ the also concluded that no increase in reports of VTEs was seen task force recommends measurement of full blood count and for filgotinib (100 mg and 200 mg doses) compared to pla- differential, transaminases, renal function, at 1 month and 3 cebo or comparators (MTX, ADA). Importantly, however, months and then periodically such as every 3 months plus additional data by pharmacovigilance activities have been lipid levels just at 3 months. required by EMA. Blood count: Haemoglobin change of less than or equal to Taken together, these observations elicited warnings (in some 20g/L decrease and haemoglobin levels greater than or equal countries "black box" warnings) for VTE in the labels of all to 90g/L do not require dose adjustment. Greater than a approved JAKi, plus additional warnings issued by the reg- 20g/L decrease or a haemoglobin of less than 80g/L (con- ulators (see above). In particular, the EMA recommends the firmed by repeat testing) should lead to dose interruption use of tofacitinib in patients with RA ‘above the age of 65 until haemoglobin values have normalised. Filgotinib leads only when there is no alternative treatment’.53 55 Such age to small dose dependent average increase in haemoglobin considerations have not been set in place for other JAKi that levels, compared with all other JAKi. 3 have similar VTE warnings in their label; however, data on Absolute counts over 1000/mm require no dose 3 outcomes studies in patients with cardiovascular risk factors adjustment, however, a count of 500–1000/mm on two are not available for those other agents. VTEs on baricitin- sequential measures suggest dose reduction or temporary 3 ib also occurred in patients with risk factors, such as obe- cessation until count above 1000/mm when JAKi can be sity, and several continued therapy, although mostly under recommenced. 3 anticoagulation.120 Absolute counts over 750/mm require no dose 3 While the overall risk of VTE is age dependent and in the adjustment, a count of 500–750/mm on two sequential order of 1:100–1:1000 (occurrence rate 0.25/100 patient measures suggests a dose reduction or temporary cessation 3 years), this risk is about doubled in patients with RA.55 until the count is greater than 750/mm to allow recom- Further research is needed to delineate the mechanisms how mencement. There is some evidence that lymphocyte counts 3 JAKi increases VTE rates (and how this compares to patients below 500/mm significantly increase the risk of opportun- with RA in general), while we also lack understanding how istic infection. glucocorticoids, Cox2 inhibitors, oral contraceptives, tamox- : Transaminases should be periodically ifen, , antipsychotics elevate VTE risk. In any monitored. Tofacitinib should not be used in severe hepatic event, careful consideration should be given as whether or impairment (Child Pugh C) nor should upadacitinib. Mild not to start a JAKi in any patient who may be at risk for a hepatic impairment (Child Pugh A) requires no dose adjust- http://ard.bmj.com/ VTE. ment. In case of moderate hepatic impairment (Child Pugh With respect to major adverse cardiovascular events (MACE) B) the tofacitinib dose should be reduced to 5 mg once a day. across indications, in randomised controlled trials and long-­ Renal function: Creatinine should be assessed periodical- term extensions no increased risks have been observed. As ly. In mild to moderate chronic renal impairment (CrCL indicated above, a long-term­ study of tofacitinib in RA pa- 50–80 mL/min) no dose adjustment is needed; with CrCL tients with cardiovascular risks is ongoing and has hitherto 30–60 mL/min, baricitinib should be reduced to 2 mg daily. on September 29, 2021 by guest. Protected copyright. not shown evidence for an increase in MACE (regarding in- With severe renal impairment (CrCl <30 mL/min) tofacitinib crease in VTEs see above). dose should be reduced to 5 mg once daily and baricitinib not 5. Laboratory abnormalities without clinical sequelae in the used at all. majority of patients: CPK elevations are occasionally seen Acute phase reactants: For evaluation and definition of re- without weakness, thus far with occasional myalgia,121 122 sponse be aware that CRP and ESR may be reduced inde- but usually without clinical repercussions, although one pa- pendently of reduction of disease activity and, therefore, tient has had rhabdomyolysis.123 Thus, in the rare event of consideration should be given to the use of disease activity symptoms, CPK should be tested, although in general this is scores that do not include inflammatory markers (such as not necessary. While the underlying cause is unknown and CDAI in RA; see below under 3). there have been suggestions this may be due to a renal tu- Lipid levels should be assessed approximately 3 months after bular effect, there are some data suggesting this effect might JAKi commencement and if increased should be managed ac- be due to restoration of muscle development with associated cording to national guidelines. CPK elevations (an event that is suppressed by 2. Consideration should be given to an annual formal skin check whose signalling depends on JAKs).124 125 Creatinine increas- as evidence suggests an increased risk of NMSC with tofac- es have also been observed but without organ dysfunction or itinib, possibly due to prior exposure to MTX and TNFi.127 other clinical sequelae, such as hypertension. 3. Disease activity should be monitored regularly using vali- Finally, gastrointestinal perforation has been reported in clin- dated composite measures of disease activity that include ical trials and may be a risk of bariticitinb and tofacitinib126 (and joint counts in order to assess if improvement by >50% was possibly other JAKi). Thus, JAKi should be used with caution in seen within 3 months and the treatment target by 6 months

Nash P, et al. Ann Rheum Dis 2020;0:1–17. doi:10.1136/annrheumdis-2020-218398 11 Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218398 on 6 November 2020. Downloaded from Recommendation

(treat-­to-­target),128 129 in line with current management rec- ommendations for RA and PsA,2 44 and in line with recom- Box 1 Research agenda mendations for other IMIDs, respectively. It should be borne 1. What is the efficacy and safety of switching between JAK-­ in mind that acute phase reactant levels may be reduced by inhibitors in non-­responders or due to lack of tolerability? JAKi independent of clinical improvement and, therefore, 2. What are the predictors of response to JAK-­inhibitors as scores that are heavily weighted on acute phase reactants, 130 compared to other DMARDs used for RA? such as the DAS28, should not be used for follow-­up. 3. What is the effect of JAK-­inhibitors on comorbidities of IMIDs including cardiovascular disease and osteoporosis? Consideration of patient preferences 4. Is VTE a class effect or a JAK inhibition effect and what is In rheumatology, there is still a substantial number of patients the mechanism of VTE? What is the actual risk of VTE when with suboptimal outcomes or who are faced with uncontrollable treating with a JAK-­inhibitor? Is the effect confined to RA or disease symptoms. They fail to respond adequately to existing observed in other indications? DMARDs. Therefore, the advent of DMARDs with a new mode 5. What is the long-­term safety from real-­world data for JAK-­ of action is welcome. The oral route may enable some patients inhibitors? For which patients should JAK inhibitors be to become more independent from hospital or health profes- contraindicated on basis of risk (particularly for VTE), and sionals compared with subcutaneous injections or infusions and should prophylaxis be considered? also appeals to those with a needle phobia; on the other hand, 6. What is the safety of JAK-­inhibition in patients with prior, some biological agents are only administered monthly or even current or who develop a malignancy whilst on therapy? less frequently and this may be seen as an advantage compared 7. Are JAK-­inhibitors effective and safe as therapy for with taking a drug once or twice daily. Cost considerations are autoimmune diseases induced by checkpoint inhibitors in an overarching principle in RA treatment recommendations patients with malignancy? and thus part of treatment decisions; while the costs of JAKi 8. How safe are JAK-­inhibitors in Hepatitis B, C, SARS-­CoV-2 are currently usually higher than those for biosimilars, this may infected patients and also other viral infections? change once these drugs become generic. Careful consideration 9. How safe are JAK-­inhibitors in pregnancy and lactation? of initiation and open communication with the patient are What should be recommended if a woman taking a JAK-­ warranted. The prescription of JAKi may not be at the expense inhibitor becomes pregnant? of attention to safety risks and must be in line with existing 10. Safety of JAK-­inhibitors in elective surgery—should they be specialty guidelines for management and good clinical practice discontinued and if so for how long and when should they which also includes the need for regular laboratory monitoring be restarted? even in patients receiving JAKi monotherapy. These points to 11. What is the efficacy of JAK-­inhibitors in extra-­articular consider contain important information for patients. A patient RA manifestations including vasculitis, nodulosis, overlap version or a decision tool will support patients to weigh poten- syndromes? tial benefits, harms and their personal goals and preferences, 12. What is the efficacy of JAK-­inhibitors in connective tissue and subsequently strengthen their role in the decision-making­ diseases such as SLE, inflammatory myositis and systemic process. sclerosis? 13. What is the efficacy and safety of combination therapies Research agenda with JAK-­inhibitors and bDMARDs in patients with severe

The committee felt that many questions remained open and RA or other diseases? http://ard.bmj.com/ needed to be addressed in future research in both adult and 14. What are the molecular in vivo down-­stream effects of JAK-­ paediatric populations. These questions are pertinent to all JAKi inhibition in the setting of individual diseases? and are presented in box 1. 15. What are the differences between different JAK-­inhibitors regarding efficacy and safety? 16. What is safety of JAK inhibitors in patients over 65 years? DISCUSSION Similar to the situation with bDMARDs 15–20 years ago, real-­ on September 29, 2021 by guest. Protected copyright. world experience with JAKi is limited. Therefore, this task force was formed which consisted of experienced clinical trial- focus on selected portions to obtain pertinent information. ists and people involved in treating patients with IMIDs across several medical areas and across nations and continents as well Currently baricitinib, filgotinib (in Europe and Japan), pefi- as patients and a health professional. The task force set out to citinib (in Japan), tofacitinib and upadacitinib are licensed for provide the readers with comprehensive guidance on the use one or more autoimmune inflammatory diseases. The consensus of this novel class of targeted therapies regarding efficacy and statement is primarily based on the evidence derived by an SLR43 safety, based on evidence and complemented by expert opinion. from clinical trials and some observational studies, whereby In this consensus statement points to consider are provided for safety aspects can currently be primarily or solely derived from the use of JAKi across IMIDs for which they are approved or information of the controlled and extended trial periods of the may be approved in the near future. drugs. The consensus statement is designed to support physicians Indeed, efficacy data from comprehensive clinical trial and other health professionals treating patients with IMIDs programmes but hardly any long-­term registry data from clin- as well as patients themselves and other stakeholders, such as ical practice are available on safety aspects . However, trial effi- hospital administrators and payers, with an up-to-­ ­date summary cacy and safety data are constantly being expanded, as are the on the thoughtful application of JAKi. Where there is occa- indications. At present five available JAKi are approved for use sional redundancy in the paper, it derives from the fact that in RA patients, but tofacitinib is already licensed for PsA and certain pieces of information relate to more than one chapter UC and other compounds will also likely receive approval for of this consensus statement, thus allowing readers who only a range of indications. Thus, JAKi may arrive at a similarly

12 Nash P, et al. Ann Rheum Dis 2020;0:1–17. doi:10.1136/annrheumdis-2020-218398 Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218398 on 6 November 2020. Downloaded from Recommendation broad or even broader list of indications across IMIDs as TNF-­ of randomised controlled trials that the risk should be balanced blockers. However, their broad efficacy is unrelated to inhibition across study arms and if one arm differs, one may conclude that of TNF signalling, but rather due to the fact that the intracellular the results are a consequence of the respective treatment. Further blockade of JAKs relates to cytokines that are distinctly involved research activities in this area are urgently needed. in different IMIDs, such as IL-6 in RA, IL-23 in PsA, PsO and Since the time of the SLR, the task force meetings and the IBD, or interferons in other diseases. Moreover, even if none start of preparing this manuscript, the COVID-19 pandemic has of the cytokines activating the JAK-ST­ AT pathway is known to struck the world. Many patients with IMIDs who are treated be of significance in the pathogenesis of a particular disease, with bDMARDs or JAKi have contracted this viral disease. such as axial spondyloarthritis, it is possible that there are syner- Currently, there is insufficient knowledge about the risks (or gistic inhibitory effects by interfering with signalling of several potential benefits) of immunomodulating drugs in these patients cytokines that individually are only minimally pathogenetically in either altering susceptibility to infection, or in determining relevant, culminating in clinical efficacy. Moreover, JAKi also disease progression once infected with SRAS-CoV2.­ Case reports interfere with the consequences of JAK activation induced by and individual centre’s experiences do not yet suggest that these cytokines that do not directly use the JAK-ST­ AT pathway for patients are at increased risk of having an adverse outcome of signalling, such as TNF, which can activate IL-6 and interferons COVID-19. However, as yet no systematic analyses have been downstream of their primary effects, thus affecting various 39 performed to inform physicians whether JAKi therapy may be pathogenic pathways. continued or should be stopped prior to or during infection. There are some differences between the drugs which are due Regardless, since these patients may be at an increased risk, to different selectivities regarding JAKi when looking at both in primary prevention should be stressed with rigorous application vivo and in vitro data, spanning from predominant JAK1 inhibi- of recommended public health and behavioural measures applied, tion (filgotinib) to pan-J­AKi (peficitinib, tofacitinib); these may including physical distancing, wearing masks and hygienic translate into differences in reversible cytokine inhibition over measures as recommended by most governments worldwide. the dosing period. These differences will be dose dependent19 Prophylactic discontinuation of an effective anti-inflammatory­ and may be reflected in variability in safety but also aspects of or immune modulatory therapy is not recommended at this efficacy. time.134–136 However, if therapy has been temporarily ceased Recommendations on indications and dosages can easily be derived from the clinical trials and labels of the respective drugs in IMID patients with proven COVID-19 infection, when to as stipulated by regulators, but the presumably more important safely recommence therapy is also not known for patients that items within this consensus statement relate to contraindications, have recovered. It is suggested that when oropharyngeal PCR pretreatment screening, safety and risks as well as monitoring and swabs are negative virus shed after a further 7 days may be 137 follow-up­ examinations. All these items have been addressed. non-­viable. The recommendations may change once further pharmacovigi- To better understand the consequences of COVID-19 on lance and registry data become available. They may also change IMID patients with and without specific therapies, it is critical once more information becomes known regarding pathways to to enter patients infected with SARS-CoV2­ into relevant regis- 138–140 disease or pathways leading to adverse events. Of note, the task tries and several exist. Of note, JAKi has been suggested force was informed by, and developed its recommendations based to be potentially beneficial against COVID-19, particularly in on, a detailed SLR evaluating studies that were published until the context of the cytokine release syndrome like hyperinflam- the end of 2018; however, since then additional safety aspects mation which occurs in a small subset of patients, and several became known from information provided by regulators, but the trials are currently ongoing to learn whether this approach has http://ard.bmj.com/ trial(s) on which this new safety information is based have not positive, negative or neutral effects.141–144 A rationale for the yet been published. Thus, the task force went beyond the data potential efficacy of baricitinib has been recently provided by provided in the SLR and addressed publications and regulatory Stebbing et al and based on predicted interference with viral communications that appeared after the end of the SLR period trafficking.145 However, answers to the clinical validity of these to provide readers with the most up-­to-­date material. hypotheses must come from observational studies as well as Among the adverse events, some have been expected from properly performed clinical trials. on September 29, 2021 by guest. Protected copyright. knowledge regarding blockade of cytokines that use JAK-ST­ ATs In summary, JAKi are a new class of agents for the treatment for signalling, such as an increased risk of serious (including of a variety of IMIDs with efficacy in many indications that is at opportunistic) infections. Others go beyond expectations but are least as good as that of bDMARDs and with an acceptable safety explained by the pharmacologic effects of the drugs, such as the profile. Given their non-protein­ nature, antidrug antibodies and increase in herpes zoster rates. The failure to reverse anaemia thus a potential secondary loss of efficacy would not occur. It of chronic disease would also be in line with expectations based is anticipated that based on these qualities and on the fact that on inhibition of JAK2, and this conclusion is confirmed by the they can be taken by the oral route their use will significantly improvement of anaemia when a more selective JAK1 inhib- increase over time. The presented consensus statement may be 131 itor is applied. However, even if relatively rare and associ- particularly helpful to those prescribing these drugs who aim to ated with known risk factors, the occurrence of VTEs and PEs achieve the most appropriate and optimal use of these therapies. is an unexpected and hitherto unexplained event requiring further information and elucidation. It is not clear if idiosyn- Author affiliations cratic platelet activation, changes in procoagulant or fibrinolytic 1School of Medicine, Griffith University, Brisbane, Queensland, Australia activity, or abnormal endothelial activation might be involved. 2Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, 1090 Vienna, Austria However, other tyrosine kinase inhibitors may activate proco- 3 agulant activity132 which might be related to changes in or Dept. Med./Rheumatology and Clinical , Charite Univ. Hospital, Berlin, 133 Germany lipoprotein levels. During the deliberations of the task force, 4Hopital Cochin, Rheumatology, Université Paris Descartes, Paris, France comments arose that the control arms of some pivotal studies 5Department of Medicine, Southwestern University of Texas, Dallas, Texas, USA had an unusually low IR of VTEs; nonetheless, it is the nature 6Hietzing Hospital, Wien, Austria

Nash P, et al. Ann Rheum Dis 2020;0:1–17. doi:10.1136/annrheumdis-2020-218398 13 Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218398 on 6 November 2020. Downloaded from Recommendation

7Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, grant support from Janssen, GSK and and honoraria for consultations and/ UK or speaking engagements from Janssen, Pfizer, Sanofi, Abbvie and Lilly. TT received 8Medicine, Division of Rheumatology, The University of Western Ontario, London, grants from Astellas, AbbVie GK, Eisai; speaking fee from: AbbVie GK, Eli Lilly Japan, Ontario, Canada Astellas, Eisai, Gilead, Pfizer Japan; and consultancy fees from: Astellas, AbbVie GK, 9Rheumatology, Leiden University Medical Center, Leiden, The Netherlands Gilead. YT has received speaking fees and/or honoraria from Daiichi-­Sankyo, Eli Lilly, 10Section for Outcomes Research, Center for Medical Statistics, Informatics, and , YL Biologics, Bristol-­Myers, Eisai, Chugai, Abbvie, Astellas, Pfizer, Sanofi, Intelligent Systems, Medical University of Vienna, Vienna, Austria Asahi-­kasei, GSK, Mitsubishi-­Tanabe, Gilead, Janssen and has received research 11Rheumatology, Keio Univ, School of Medicine, Tokyo, Japan grants from Mitsubishi-­Tanabe, Chugai, Abbvie, Takeda, UCB, Daiichi-­Sankyo, Eisai. 12Division of Gastroenterology and Hepatology, Department of Medicine 3, Medical MT: Speaker for BMS, Falk Foundation, Gilead and MSD; advisory boards for Albireo, University of Vienna, Vienna, Austria BiomX, Boehringer Ingelheim, Falk Pharma GmbH, Genfit, Gilead, Intercept, MSD, 13Oregon Health Sciences University, Portland, Oregon, USA Novartis, Phenex and Regulus. He further received unrestricted research grants from 14Medical Humanities, Amsterdam University Medical Centre, Amsterdam, Albireo, Cymabay, Falk, Gilead, Intercept, MSD and Takeda. He is also co-­inventor Netherlands of patents on the medical use of norUDCA (filed by the medical University of Graz 15Rheumazentrum Ruhrgebiet, Herne, Germany as previous employer). FvdB received consultancy and/or speaker fees from Abbvie, 16Dermatology, University Hospitals of Geneva, Geneva, Switzerland Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer and UCB. 17Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK MdW has received honoraria for consultancies and speaking through Stichting Tools 18Musculoskeletal Research Group, Newcastle University, Newcastle upon Tyne, UK from AbbVie, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, Roche. RW: honoraria 19Rheumatology, Albany Medical College, Albany, New York, USA for speaking engagements and advice from Galapagos, Gilead and Celltrion. KLW 20Internal Medicine, Seoul National University College of Medicine, Seoul, Korea (the received grant support from BMS and Pfizer and honoraria for consultations and /or Republic of) speaking engagements from Pfizer, BMS, Abbvie, Gilead, Galapagos, Lilly, GSK, UCB. 21Medicine, University of Alberta Faculty of Medicine and Dentistry, Edmonton, RX received consultancy and/or speaker fees from Abbvie, Lilly, Pfizer, UCB, Janssen. Alberta, Canada 22 Patient and public involvement Patients and/or the public were involved in the Department of Medicine & Therapeutics, Chinese University of Hong Kong Shaw design, or conduct, or reporting, or dissemination plans of this research. Refer to the College, New Territories, Hong Kong Methods section for further details. 23First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan Patient consent for publication Not required. 24 Rheumatology, University Hospital Gent, Gent, Belgium Provenance and peer review Not commissioned; externally peer reviewed. 25KU Leuven University Hospitals Leuven, Leuven, Belgium 26Division of Rheumatology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which Contributors All authors participated in the disucssions and in the work on the permits others to distribute, remix, adapt, build upon this work non-­commercially, manuscript and its revision. and license their derivative works on different terms, provided the original work is Funding This research was funded by AbbVie and . properly cited, appropriate credit is given, any changes made indicated, and the use is non-­commercial. See: http://​creativecommons.org/​ ​licenses/by-​ ​nc/4.​ ​0/. Disclaimer The views expressed in this paper are those of the authors and not necessarily those of any of the individuals’ employers or funders. Readers should be ORCID iDs aware and the authors realise that in the future new and possibly conflicting data Peter Nash http://orcid.​ ​org/0000-​ ​0002-2571-​ ​788X will arise and there may be errors that were unknown or not realized at the time of Andreas Kerschbaumer http://orcid.​ ​org/0000-​ ​0002-6685-​ ​8873 deliberations and the writing of this paper, but look forward to updating the paper Thomas Dörner http://orcid.​ ​org/0000-​ ​0002-6478-​ ​7725 periodically as new data come to hand and research agenda items are addressed. Roy M Fleischmann http://orcid.​ ​org/0000-​ ​0002-6630-​ ​1477 Competing interests DA has received grants from AbbVie, Novartis and Roche, Janet E Pope http://orcid.​ ​org/0000-​ ​0003-1479-​ ​5302 consulting and lecture fees from Abbvie, Amgen, Celgene, Lilly, Medac, Merck Sharpe Désirée van der Heijde http://orcid.​ ​org/0000-​ ​0002-5781-​ ​158X & Dohme, Novartis, Pfizer, Roche, Sandoz and Sanofi/Genzyme. W-­HB has received Kevin L Winthrop http://orcid.​ ​org/0000-​ ​0002-3892-​ ​6947 a research grant from Pfizer and honoraria for advice from Abbvie, Alimirall, BMS, Maarten de Wit http://orcid.​ ​org/0000-​ ​0002-8428-​ ​6354 Celgene, Janssen, Leo, Lilly, Novartis and UCB. TD received study support and/or Daniel Aletaha http://orcid.​ ​org/0000-​ ​0003-2108-​ ​0030 consulting fees by AbbVie, Celgene, Eli-­Lilly, EMD/Merck, Janssen, Novartis, Pfizer, Paul Emery http://orcid.​ ​org/0000-​ ​0002-7429-​ ​8482 Eun Bong Lee http://orcid.​ ​org/0000-​ ​0003-0703-​ ​1208 Roche, Sanofi, UCB Pharma. MD: grants from Pfizer, Abbvie, UCB, Janssen, Novartis http://ard.bmj.com/ and honoraria from Pfizer, Abbvie, UCB, Janssen, MSD, Novartis, BMS, Celgene, Walter P Maksymowych http://orcid.​ ​org/0000-​ ​0002-1291-​ ​1755 Biogen, Sandoz. PE: grants from AbbVie, Novartis, Samsung, Lilly and honoraria Yoshiya Tanaka http://orcid.​ ​org/0000-​ ​0002-0807-​ ​7139 from AbbVie, Novartis, BMS, Gilead, Samsung, Lilly. XB, KG received consultancy René Westhovens http://orcid.​ ​org/0000-​ ​0002-3432-​ ​3073 and lecture fees from Novartis, Pfizer and Roche and investigational grants from Josef S Smolen http://orcid.​ ​org/0000-​ ​0002-4302-​ ​8877 Roche. EBL reports grants from Green pharma, Seoul, grants from Handoc, Seoul, and personal fees from Pfizer. PTN has received research grants and funding for clinical REFERENCES trials and honoraria for advice and lectures on behalf of Abbvie, BMS, Boehringer 1 Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the Ingelheim, Celgene, Eli-­Lilly, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi,

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